IN SITU GEL FOR THERAPEUTIC USE

Abstract: Pharmaceutical drug delivery composition, especially for ophthalmological use, comprising: a liquid hypotonic solution of at least one hydrophilic polymer of the type which undergoes liquid-gel phase transition gelling in situ in contact with a physiological solution, and a pharmaceutically active compound, as well as the use thereof for local administration of drugs.

Description: In situ gel for therapeutic use. The present invention is related to the field of slow release drug delivery systems for therapeutic use, especially in the ophthalmic field, and provides an aqueous liquid composition which in contact with a physiological solution forms a gel matrix which has been found to stay for a considerable time in the administration area, for instance the eye, without causing any problems to the patient. This gel can be utilized for controlled continuous administration of drug over a prolonged period of time. A composition according to the invention can be used in a number of situations, e.g. oral, buccal, nasal and vaginal administration, when a slow release system is advantageous but will in the following be discussed mainly in connection with it's ophthalmological use since the requirements here are especially high. There are a number of situations when topical administration of a drug to the eye would be the most efficient form of therapy and various drop solutions have been developed for this purpose. However, natural mechanisms such as tear rates and blinking, which are important for the protection of the eye by removing dust and contaminants from the surface of the eye, make drug delivery difficult. A fairly large group of patients have considerable problems to instill a solution onto the eye by themself and the need for slow release systems has therefore been recognized for a long time. There are also a number of therapeutic situations where the efficacy of the drug would benefit from a prolonged occular contact time. According to one concept a solid implant containing the active drug is manufactured and delivered to the doctor or nurse for application onto the patient's conjunctiva, preferably under one of the eye lids. These type of implants often have an outer membrane layer through which the drug is allowed to diffuse. The release rate depends on the membrane structure as well as the internal matrix in which the drug is incorporated. According to another concept a composition which at room temperature and below this value is liquid (non-solid) is instilled into the eye and due to the rise in temperature forms a polymer matrix, for instance a gel. A somewhat similar approach utilizes the fact that certain polymer solutions in contact with salt ions form a gel. Some systems have been disclosed which are physiologically acceptable and which form a gel in contact with a physiological salt solution, for instance a tear solution. It is readily appreciated that according to this concept potentially very useful systems for drug delivery are provided. Laboratoires Merck, Sharp & Dohme-Chibret have in a series of patent applications described the use of components which undergo liquid-gel phase transition under the effect of an increase in the ionic strength, see for instance AU8663189, EP227494, EP424042 and EP437368. In EP227494 it is mentioned that the test substance fluorescein is still persisting 5 hours after instillation when administered in such a composition. In these publications an extracellular anionic heteropolysaccharide produced by the bacterium Pseudomonas elodea, known by the name of gellan gum and marketed under the brand name Gelrite™, is presented as the most preferred gel formation component. An aqueous solution of the gel-forming components is prepared containing no or only a very small amount of ionic substances together with the drug in a suitable form and optionally a preservative. It is also pointed out that the non-solid composition should preferably be isotonic and a tonicity adjusting substance, for instance annitol, is added. We have now surprisingly found that considerably improved drug delivery systems are obtained if compositions of the type mentioned above in contrast to the teaching of the prior art are made hypotonic. Gels formed under these conditions have been found to stay considerably longer in the eye compared to gels formed at higher tonicity values, e.g. under isotonic conditions, hence providing a more efficient delivery system. The invention is accordingly related to a liquid hypotonic ophthalmic solution comprising a pharmaceutically active drug and at least one hydrophilic polymer of the type which undergoes liquid-gel phase transition gelling in situ in contact with the physiological solution, for instance tear solution or humour solution when used for intraocular administration. In another aspect of the invention a method for administration of a drug is provided using a composition as defined in this specification. The hydrophilic polymer is functionally defined by the ability of an aqueous solution of the polymer to form a solid polymer structure, for instance a gel, when the ionic strength is raised to physiological values. Examples of components belonging to this group include polysaccharides and natural as well as synthetic polysaccharide derivatives. The preferred component at present is an extracellular anionic heteropolysaccharide produced by the bacterium Pseudo onas elodea, known as gellan gum and marketed as Gelrite™. The gel forming component may in more general terms be any component which before administration is a liquid but forms a gel upon contact with a physiological fluid due to exchange of components between said liquid and the physiological fluid. Such exchange of components include but is not limited to proteins, such as lysozymes, and ionic components as discussed above. The concentration of the gel forming component in cases when Gelrite is used is preferably in the range of from 0.1 to 10 % by weight, especially 0.1-2 % by weight. The inventive concept is as mentioned above that the non- solid composition containing the hydrophilic polymer solution is hypotonic. It has been found, however, that the tonicity should not be too low since this causes undesirable side- effects, such as more or less severe initial irritation when the composition is applied. The osmolality of the non-solid composition should accordingly be lower than that of an isotonic solution (about 290 mOs/kg) and a selected range according to this invention is from about 25 - 200 mOs/kg, preferably 25-150 mOs/kg and especially 50-150 mOs/kg. The at present most prefered composition has a value around 100 mOs/kg. The drug component contained in the composition should preferably be present as a dispersive system, either as a suspension of particles or as an emulsion. The drug could be incorporated in or associated with carrier substances in the form of particles e.g. polymers (biodegradable, non- biodegradable or polymers which dissolve or degrade upon contact with a physiological fluid) , lipids or ion-exchange resins. In EP424042 is disclosed a system based on compositions of the Gelrite type in which the drug is present in particles which dissolve due to change in pH when the composition is instilled into the eye. The pH and the buffering capacity of the composition being such that the neutralizing action of lachrymal fluid is sufficient for dissolving the solid microparticles. Examples of methods for producing lipid particles containing an ophthalmologically active substance are given in EP 437368. The drug component contained in the composition could also be present as a solution. It may be solubilized by surfactants, lipids or by complex-forming agents. The active drug to be administered according to the present invention can be chosen among a great number of components, for instance for ophthalmological use. Examples of such components include - antihistaminics and decongestants, for instance pyrilamine, tetrahydrazoline, antazoline and analogues thereof, - anti-inflammatories such as flubiprofen, diclofenac, acetylsalicylic acid, cortisone, hydrocortisone, dexamethasone, prednisone, indomethacin and analogues thereof - antiparasitc and/or antiprotozoal compounds - antibacterial substances such as tetracyclines, penicillin, bacitracin, sulphonamides and analogues thereof, - mydriatics, for instance cyclopentanol and tropicamide - cytotoxics, for instance 5-fluorouracil - antiglaucoma drugs, for instance prostaglandins like the omega chain modified derivatives disclosed in EP0364417 (esp. 13, 14-dihydro-17-phenyl-18, 19,20-trinor-PGF2 α -isopropylester) and timolol, pilocarpine, epinephrine, dipivalylepinephrine, and their analogues. - antivirals - antioxidants - anticataracts - antiallergics - anaesthetics The composition may contain other additives such as polymers, preservatives, nonionic tonicity agents, solubilizers, buffer agents, complexing agents and chelating agents. Examples. The relevance of the concept was verified in a series of experiments in which compositions comprising Gelrite (various concentrations) Benzalkonium chloride 0.01 g and Glycerol (0 - 3%), for adjusting the tonicity, in 100 ml of ultrapure water were instilled into one of the eyes of a healthy volounteer. For measuring the duration time, or contact time, the composition also contained a small amount of fluorescent particles. The time these particles were detectable in the instillation area was measured and taken as an indication of the effectiveness of the drug delivery system. A glycerol concentration of 3% is close to an isotonic solution and represents a comparison with a prior art system. It should be noticed that with no addition of the tonicity adjusting component, glycerol, initial pain for half a minute or even more was reported by the test persons. A composition for use in the eye should for this reason have an osmolatity value of at least 25 mOs/kg. From the results presented above it can be concluded that considerably longer contact times have now been achieved compared to the results indicated in the prior art literature.

Claims: Claims 1. Pharmaceutical drug delivery composition comprising - a liquid hypotonic solution of at least one hydrophilic polymer of the type which undergoes liquid-gel phase transition gelling in situ in contact with a physiological solution, and - at least one pharmaceutically active compound. 2. Composition according to claim 1, wherein the concentration of polymer is 0.1-10 wt-%. 3. Composition according to claim 1 or 2, wherein the hydrophilic polymer is a polysaccharide, for instance gellan gum. 4. Composition according to any one of claims 1 to 3, wherein the osmolality is 25-200 mOs/kg. 5. Composition according to claim 4, wherein the osmolality is 25-150 mOs/kg. 6. Composition according to claim 5, wherein the osmolality is 50-150 mOs/kg. 7. Composition according to any one of claims 1-6, wherein the active drug is present as a solution or in the form of particles. 8. Composition according to claim 7, wherein the drug is incorporated in or associated with a polymeric matrix, complex- forming matrix, lipid matrix or ion-exchange resin. 9. Composition according to any one of claims 1-8 wherein the composition additionally contains one or more component selected from preservatives, solubilizing agents, non-ionic tonicity adjusting agents, pH-adjusting agents or complexing agents. 10. Composition according to any one of claims 1-9 which is intended for ophthalmological use and the physiological solution is lacrimal fluid or aqueous humour. 11. Method for local administration of a pharmacologically active drug characterized by the use of a composition according to any one of claims 1-10.

Inventors: CARLFORS JOHAN, EDSMAN KATARINA, CARLFORS, JOHAN, EDSMAN, KATARINA
Applicants: CARLFORS JOHAN, EDSMAN KATARINA, PHARMACIA AB, CARLFORS, JOHAN, EDSMAN, KATARINA
Application year: 1994
Main classification: A61K9
IPC codes: A61K9, A61K47